Pharmaceutical composition

ABSTRACT

The invention concerns topical formulations such as nail varnishes comprising as the active agent the compound of formula I                    
     in free base form or in acid addition salt form, together with a polymeric film former and further excipients as appropriate. It also concerns a process of preparation of such preparations by mixing with an appropriate polymeric film former and conventional further excipients as appropriate, and a method of treatment of onychomycosis.

The present application is a continuation of U.S. application Ser. No.09/215,398, now U.S. Pat. No. 6,214,360 filed Dec. 18, 1998, which inturn is a divisional of U.S. application Ser. No. 08/466,490 filed Jun.6, 1995, now U.S. Pat. No. 5,866,105, which in turn is a continuation ofU.S. application Ser. No. 8/272,711, Jul. 8, 1994, abandoned, which inturn is a continuation of U.S. application Ser. No. 08/048,153, Apr. 14,1993, now abandoned, which in turn is a continuation of U.S. applicationSer. No. 07/886,797, May 21, 1992, now abandoned.

PHARMACEUTICAL COMPOSITION

The present invention relates to topical formulations containing anallylamine compound as the pharmacologically active agent.

It concerns a topical formulation such as a a nail varnish comprising asthe active agent the compound of formula I

in free base form or in acid addition salt form, together with apolymeric film former such as polyvinyl acetate, acrylic- andmethacrylic-acid alkyl ester copolymerisates with quaternary ammoniumgroups or methylvinylether-maleic acid monoalkyl ester copolymerisatesand further excipients as appropriate.

The compound of formula I may be in free base form or in acid additionsalt form. An acid addition salt form may be prepared from the free baseform in conventional manner and vice-versa. Examples of suitable acidaddition salt forms are the hydrochloride, the lactate and theascorbate. The free base and the hydrochloride are preferred.

The compound of formula I is known from e.g. EP-A-24587. It belongs tothe class of allylamine anti-mycotics. It is known in the art under itsgeneric name as terbinafine, and it is commercially available under thetrademark LAMISIL. Apart from its efficacy against dermatophytes afteroral as well as topical administration, we have found, it is also highlyefficient after oral application in the treatment of onychomycosis, asit has a strong fungicidal activity and high affinity to the keratin ofthe nails, where it is enriched. Therefore a significantly higher curerate may be achieved than with conventional therapies such as e.g. oraltreatment with griseofulvin.

Although the compound of formula I is a very safe drug, systemictreatment of onychomycosis offers some disadvantages, e.g. exposure ofthe whole organism to the drug substance and the need for rather highdoses. Therefore the possibility of local, namely topical treatment ishighly desirable and would be preferred by many patients. On the otherhand many attempts have been made with various drugs, e.g. griseofulvin,to prepare topical formulations for the treatment of onychomycosis butthe results obtained were unconvincing. This might be related toinsufficient penetration of the drugs into the deeper layers of thenails.

It has now been found that the compound of formula I, when it isformulated in the proper vehicle, is surprisingly highly efficient upontopical application to infected nails in the treatment of onychomycosis.

Such formulations should ideally have the following properties:

As penetration into the infected nails is a rather slow process, theyshould build up a depot after application from where the drug can freelydiffuse into the nail tissue;

they should have the capacity to easily release the drug;

they should be comfortable for the patient, e.g. easy to apply, to beapplied with low frequency, easy to remove and well tolerated.

It has been found that such formulations can be obtained with thebenefits mentioned above and a high efficacy by formulating the compoundof formula I in free base form or in acid addition salt form as a nailvarnish containing one or more suitable film formers and conventionalfurther excipients as appropriate.

Components of the nail varnishes of the invention are:

1. The compound of formula I in free base form or in acid addition saltform.

2. A polymeric film former. This may be either water-soluble orwater-insoluble. Polymers suitable as water-insoluble film formers aree.g. polyvinylacetate, acrylic- and methacrylic-acid alkyl estercopolymerisates with quaternary ammonium groups andmethylvinylether-maleic acid monoalkyl ester copolymerisates. Whereasthe polymer most frequently used in nail varnishes is nitrocellulose,this polymer cannot be used in the present invention due to chemicalincompatibility with the drug substance. Polymers suitable aswater-soluble film formers are in particular polymers soluble in wateras well as in organic solvents. Such polymers are e.g.polyvinylpyrrolidone (PVP) and vinylpyrrolidone-vinyl acetatecopolymers. Preferably the mean molecular weight of these copolymers isabout 60.000±15.000. A commercially available polymer of the latterclass is e.g. known under the tradename KOLLIDON VA 64. Preferred arewater-insoluble film formers such as polyvinyl acetate or acrylic- andmethacrylic-acid alkyl ester copolymerisates with quaternary ammoniumgroups as e.g. available under the tradenames EUDRAGIT RL and EUDRAGITRS resins or methylvinylether-maleic acid monoalkyl estercopolymerisates as e.g. available under the tradename GANTREZ ES.

The compound of formula I and the polymeric film former are preferablypresent in the composition in the proportion of from about 1:0.5 toabout 1:25, more preferably of from about 1:1 to about 1:20 and mostpreferably of from about 1:1 to about 1:10 on a w/w basis.

The compound of formula I makes up from e.g. about 0.5% to about 30% ,preferably from about 1% to about 20% of the total composition on aweight basis.

In addition to the drug substance and the polymeric film former thecompositions normally contain conventional further excipients, e.g. asolvent system. This can be either aqueous or organic or a mixturebetween organic solvents and water. Organic solvents are those which arephysiologically acceptable and compatible with the drug substance andthe further ingredients of the composition. Typical solvents areethanol, isopropanol, acetone and ethyl acetate. The preferred solventsystem is ethanol, with the addition of a certain amount of water. Theamount of water is in most cases less than the amount of the solvents.Typical water/solvent ratios are e.g. below 1:3. However in some casesthe amount of water may exceed that of the solvent. It may then be e.g.up to 2.5:1.

The compositions of the invention usually also contain additionalingredients which stabilize the formulations and improve theirproperties. In particular such further excipients are:

plasticizers such as dialkylphthalates, e.g. dibutylphthalate,hydroxy-fatty acid oils, e.1g. castor oil, triglycerides and siliconoils;

film modifiers which change the properties of the main film former, inparticular improve its application properties, e.g. hardness afterevaporation of the solvent or flexibility on the nail. These modifierscan be e.g. acrylic ester resins, arylsulfonamide-formaldehyde resins,cellulose derivatives or polyamide resins;

surfactants, e.g. polyethylenglycol-alkylethers (e.g. as available undertradename BRIJ), which help solubilize the drug especially in vehiclescontaining water;

penetration enhancers, e.g. azole, dimethylsulfoxide, unsaturated fattyalcohols, surfactants and propylene glycol;

colouring agents;

antioxidants, e.g. tocopherol;

complexing agents, e.g. ethylendiamintetracetic acid (Komplexon III);and

UV-absorbers.

The topical formulations of the invention such as nail varnishes can beobtained by a process comprising mixing the compound of formula I infree base form or in acid addition salt form with an appropriatepolymeric film former such as polyvinyl acetate or acrylic- andmethacrylic-acid alkyl ester copolymerisates with quaternary ammoniumgroups or methylvinylether-maleic acid monoalkyl ester copolymerisatesand further excipients, e.g. the solvent system, as appropriate. Theprocess of the invention may be effected in conventional manner.

The compositions according to the invention are especially useful forthe treatment of onychomycosis. An indicated daily dose to beadministered typically is from about 0.05 to about 5.0 mg of thecompound of formula I per square centimeter of the treated nailmaterial. Preferred application rates are from about 0.1 to 3.0 mg persquare centimeter. The concentration of the compound of formula I in thetissue at the place of action is preferably e.g. between 0.001 and 1.0mg/g depending on the type of fungal nail infection and type of treatednails. Applications may take place once a day in severe cases or evenonly once a week. Preferably treatments are repeated every second orthird day.

Both the nail material at fingers and toes may be treated when infectedwith fungi causing onychomycosis, e.g. dermatophytes, yeast fungi ormolds.

The following examples illustrate the invention (the compound of formulaI is herein briefly named compound 1):

EXAMPLE 1 Nail Varnish 20%

Ingredient Amount (g/100 g) Compound 1 in free base form 20.00 Dibutylphthalate 0.70 Acrylic resin, hard durable 2.50 (e.g. PARALOID A-21)Polyvinyl acetate 13.50 Ethyl acetate 63.30

EXAMPLE 2 Nail Varnish 5%

Ingredient Amount (g/100 g) Compound 1 in free base form 5.0 Dibutylphthalate 0.6 50% solution of a copolymerisate of methyl- 30.0vinylether and maleic acid monobutyl ester in ethanol (e.g. GANTREZ ES425) Ethanol 30.0 Ethyl acetate 34.4

EXAMPLE 3 Nail Varnish 5%

Ingredient Amount (g/100 g) Compound 1 in free base form 5.0 Glyceroltriacetate 2.0 Oleic alcohol 2.0 50% solution of a copolymerisate ofmethyl- 40.0 vinyl-ether and maleic acid mono- ethyl ester in ethanol(e.g. GANTREZ ES 225) Water 10.0 Ethanol 94% W/W 40.98 Butylhydroxytoluene 0.02

EXAMPLE 4 Nail Varnish 5%

Ingredients Amount (g/100 g) Compound 1 in hydrochloride form 5.0Glycerol triacetate 2.0 Isopropyl myristate 2.0 GANTREZ ES 225 40.0Water 10.0 Ethanol 94% W/W 40.98 Butyl hydroxytoluene 0.02

EXAMPLE 5 Nail Varnish 5%

Ingredients Amount (g/100 g) Compound 1 in hydrochloride form 5.0Glycerol triacetate 2.0 Isopropyl myristate 2.0 copolymerisate ofacrylic- and methacrylic- 20.0 acid esters with a small amount ofquaternary ammonium groups (e.g. EUDRAGIT RL 100) Acrylic resin, harddurable 2.5 (e.g. PARALOID B-82) Water 5.0 Ethanol 94% W/W 63.48 Butylhydroxytoluene 0.02

EXAMPLE 6 Nail Varnish 2%

Ingredients Amount (g/100 g) Compound 1 in hydrochloride form 2.0 Castoroil 3.0 50% solution of a copolymerisate of methyl- 40.0 vinylether andmaleic acid mono- butyl ester in ethanol (e.g. GANTREZ ES 425) Ethanol94% W/W 55.0

EXAMPLE 7 Nail Varnish 10%—Water Removable

Ingredient Amount (g/100 g) Compound 1 in hydrochloride form 10.0Isopropyl myristate 6.0 Vinyl pyrrolidone-vinylacetate- 12.0 copolymerWater 5.0 Isopropanol 67.0

EXAMPLE 8 Nail Varnish 5%—Water Removable

Ingredient Amount (g/100 g) Compound 1 in hydrochloride form 5.0Isopropyl myristate 6.0 Vinylpyrrolidone-vinylacetate- 10.0 copolymerIsopropanol 79.0

EXAMPLE 9 Nail Solution 1%—Aqueous—Water Removable

Ingredient Amount (g/100 g) Compound 1 in hydrochloride form 1.0Polyoxyethylene-4-lauric alcohol 2 .0 (e.g. BRIJ 30)Vinylpyrrolidon-vinylacetate- 12.0 copolymer 1,2-Propylene glycol 5.0Ethanol 94% W/W 25.0 Sodium pyrosulfite 0.1 Na-EDTA 0.1 Distilled water54.8

The efficacy of the formulations of the invention can be shown in vitroor in vivo. A suitable in vitro method is measurement of the penetrationthrough excised nails where it can be shown that fungicidally effectiveconcentrations of the drug are reached also in deeper layers of the nailtissue. A further in vitro method is the measurement of the dissolutionrate of the drug from a dried varnish layer where it can be shown thatfungicidally effective amounts of the drug are sufficiently releasedfrom dried varnish layers. In vivo the most convincing test is thedouble blind study with onychomycosis.

What is claimed is:
 1. A topical nail varnish formulation for thetreatment of onychomycosis of the nails comprising 1) an active agent offormula I

in free base form or in acid addition salt form; and 2) awater-insoluble film-former.
 2. A formulation according to claim 1wherein said water-insoluble film-former allows penetration of theactive agent of formula I into the keratinized ungular layer of thenail.
 3. A formulation according to claim 1 further comprising asolvent.
 4. A formulation according to claim 1 wherein said active agentof formula I is in the form of its hydrochloride salt.
 5. A method oftreatment of onychomycosis comprising administering a pharmaceuticallyeffective amount of a formulation according to claim 1 to a patient inneed of such treatment.